This research is directed in two areas: studies of damage to critical target genes in environmentally-associated cancers and studies of genetic susceptibility and gene-environment interaction in disease risk. The research on critical target genes tests the hypothesis that environmental exposures produce specific patterns of gene mutation in human tumors. The research on genetic susceptibility tests the hypothesis that commonly inherited allelic variants of certain genes, in conjunction with environmental exposures, affect a persons risk of developing disease. In work on critical target gene damage we have recently published our study comparing the pattern of p53 mutations in bladder tumors from arylamine- exposed and unexposed people (Taylor et al. 1996). We suggest that, although p53 is frequently mutated in these tumors, it does not appear to be a critical target gene in arylamine-associated bladder carcinogenesis and that there must be other critical target genes. Interestingly, we found that tumors from both exposed and non-exposed people have a high frequency of multiple p53 mutations and that such multiple mutations are frequently concordant (e.g. both A to G). This pattern of mutation could reflect a defect in DNA synthesis or repair. In work on genetic susceptibility, we have recently submitted for publication a study showing that men who are homozygous for the inherited allelic variant of the VDR (that correlates with high serum levels of vitamin D) have one third the risk of developing prostate cancer as men who carry one or more copies of the wildtype allele. Our findings indicate that among controls, 23% of whites are homozygous for the variant while among blacks it is only 8%. If verified, the VDR polymorphism represents an important determinant of prostate cancer risk and suggests vitamin D supplementation as a possible means of primary prevention.